Laureates 2015 - 2016

Title of the project: Benefit of proton therapy in the treatment of non-metastatic head and neck cancer – Prospective evaluation of the efficacy, toxicity and cost-effectiveness of proton therapy compared to photon therapy

Summary of the project: Cancers of the head and neck are a common entity, whose epidemiology changes with the appearance of virus-induced cancers. Current treatments allow high cure rates in many clinical situations, but often cause severe long-term toxicities , which are responsible for an impaired quality of life of patients and are potentially life-threatening , despite the use of advanced radiotherapy techniques. The use of new modalities of radiotherapy, including proton therapy, helps protect healthy organs, reduce late toxicity and thus improve long-term quality of life. There is not at present comparative data of adequate quality between proton and conventional photon radiotherapy. The objective of the course is to carry out an analysis of the effectiveness, toxicity and quality of life in a prospective cohort of patients with head and neck cancer treated with proton therapy at MD Anderson Cancer Center. The comparison with a matched cohort of patients treated with conventional radiotherapy at MDACC will provide a first comparison between the two techniques. It will be possible to draw a cost-effectiveness analysis of proton therapy and select the ideal candidates that can benefit from this advanced technology. The transposition of these results in the context of European health systems will also provide important arguments in the debate on the introduction of proton therapy centers in Europe.

Summary of the project: Normal tissue (NT) toxicity is a dose limiting parameter of successful anti-cancer treatment. Recent studies performed in our lab showed that delivery of RT at ultra-high dose rate could spare healthy tissues while keeping anti tumor efficacy thus opening the possibility to treat tumours at very high doses without complication. This new type of radiotherapy is called Flash RT and based on dose delivery at a dose rate 1000 fold higher than Conventional RT (Conv) used currently in the clinical practice. My project is at the crossroads of three areas of research: radiotherapy (RT), tumour immunology and lung adenocarcinoma. I will study Flash effect on NT and intra-tumour immune infiltration in Lox-STOP-Lox-KrasG12D;p53(Flox/Flox) C57NL/6J mice that develop spontaneous lung tumours. I will investigate immune contribution to Flash RT efficacy and establish new pertinent combination of treatment with immunotherapy. Clinical trials using Flash technology will be the ultimate goal.

Title of the project: Molecular characterization of EZH2-associated prostate cancer and epigenetic therapy approaches

Place of the training course: Rubin lab and Institute for Precision Medicine, Weill Cornell Medical College, New York

Summary of the project: Prostate cancer remains an important cause of cancer-related death in men in Western countries. In a subset of metastatic cases, resistance to anti-androgen therapies occurs through a switch of the tumor phenotype towards neuroendocrine prostate carcinoma (NEPC), which is particularly aggressive. This phenotype switch could be explained by genetic events, but also by epigenetic alterations, which can be induced by a deregulation of chromatin remodelers such as the Polycomb repressive complex 2 (PRC2). Interestingly, it has been shown that Enhancer of zeste homolog 2 (EZH2), a key subunit of PRC2, is highly overexpressed in NEPC.
In this study, we will readdress EZH2 expression levels in NEPC as compared to castration-resistant and hormone-sensitive prostate adenocarcinomas. We will next study the effects of pharmaceutical EZH2 inhibition in these tumors using cell lines, but also patient-derived tridimensional tumor models. We will characterize gene expression profiles and the underlying epigenetic landscape (DNA methylation and the histone mark H3K27me3) of EZH2-high prostate cancers. Lastly, we will check how these profiles are influenced by EZH2 inhibition.
EZH2 inhibitors are currently being developed in early phase clinical trials. Thus, the results of this study could encourage proposing a clinical trial for patients suffering from this aggressive form of prostate cancer.

Summary of the project: Efficiency of conventional cancer treatment such as chemotherapy, radiation or targeted therapy has recently been associated with an immunogenic cell death that promotes the development of immune responses against cancer cells. We therefore anticipate that the comprehension of the mechanisms leading to immunogenicity of cell death will have a profound impact on the design of anticancer therapies in relation with the recent success of immunotherapy. The present project will study the immune response induced by the combination of p53 re-inducers and Raf inhibitors in melanoma. This combination is thought to be more effective than single agent approaches. The immunogenicity of the combined therapy will be assessed in collaboration with the Department of Melanoma and Immunotherapeutics at the Memorial Sloan-Kettering Cancer Center. We will perform various sets of analysis on melanoma mouse model and biopsy from patient treated by such combination in a clinical trial. We will characterize the immune infiltrate and the inflammatory molecule at each step by using immunochemistry, Elisa, polychromatic flow cytometry as well as the evaluation of treatment-induced neoantigen-specific T-cell reactivity on the basis of cancer exome data. The results of such analysis will further feed the rational to combine these therapies with immunotherapy to enhance more immune clearance and prevent relapsing of the disease.

Title of the project: Alteration of the PTEN signaling network as a predictor of the development of metabolic liver disorders and hepatocellular carcinoma in chronic hepatitis C.

Place of the training course: Services of Gastroenterology and Hepatology and of Clinical Pathology, Geneva University Hospitals 4, rue Gabrielle-Perret-Gentil CH – 1211 Geneva 14

Summary of the project: Hepatitis C virus (HCV) infection is a major health problem due to its high prevalence, and the associated morbidity and mortality. The clinical progression of hepatitis C is influenced by several cofactors like the metabolic syndrome. A common feature is steatosis, observed in up to 70% of chronically HCV-infected patients, it represents an important risk factor for the development of liver fibrosis and cancer. In patients infected with HCV genotype 3 steatosis correlates with viral replication levels and disappears after successful antiviral therapy. Recently, the host laboratory has demonstrated that in patients chronically infected with the highly steatogenic HCV genotype 3a, the expression of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is significantly decreased through post-transcriptional mechanisms in the hepatocytes. PTEN is a tumour suppressor, the pathological dysregulations of its expression/activity in hepatocytes not only causes steatosis but may also promotes the progression of liver diseases towards cancers such as HCC.
The main aim of this project is to investigate the relevance of alterations of PTEN and its signalling network as a prognostic and predictive factor for the development of metabolic liver disorders and HCC in (i) in vitro models of HCV infection and/or protein expression, and (ii) in human liver biopsy samples.

Title of the project: Intravital microscopy analysis of superparamagnetic iron oxide nanoparticles locally delivered using convection-enhanced delivery in an orthotopic xenograph model of human glioblastoma multiforme in mice.

Summary of the project: Glioblastoma multiforme is one of the most aggressive cancers, with a life expectancy of 14.6 months with chemoradiation treatment after surgical removal of the tumor. This poor prognostic is coupled with high invasiveness and almost inevitable recurrence, very often near the site of the original tumor. Furthermore, glioblastoma multiforme is radioresistant and, in large part due to the blood-brain barrier, chemoresistant. Locally delivered treatments seem to a promising direction in treating glioblastoma multiforme. During these last few years, local delivery techniques have improved, notably with the development of convection-enhanced delivery. Simultaneously, nanotechnologies have advanced, with numerous promising applications in cancer treatment. We propose to conduct an in vivo study of the mechanisms of locally delivered superparamagnetic iron oxide nanoparticles (SPION). We will use intravital microscopy to describe SPION effects on an orthotopic xenograft model of human glioblastoma multiforme in nude mice.

Summary of the project: Post-transplant lymphoproliferative disorders (PTLD) are a major issue in transplantation medicine and contribute significantly to morbidity and mortality of transplant patients. Compared to diffuse large B-cell lymphomas (DLBCL) arising in a non-immunocompromised host, monomorphic PTLD have a poorer prognosis and higher mortality rates.
So far, little knowledge exists whether PTLDs respond differently to lymphoma treatment than non-transplanted patients. It is also not known if PTLDs differ at the genetic and epigenetic level from lymphomas arising in non-immunocompromised hosts. The paucity of data considering common mutation profiles or DNA methylation patterns of PTLDs highlight the need for further research focusing on their pathogenesis.
We intend to comprehensively characterize PTLDs on genetic and epigenetic levels using Next Generation Sequencing (NGS) and methylation analysis. These results might pave the way for a better pathogenetical understanding of PTLDs as well as improved treatment strategies using targeted therapy.
Based on the joint cohorts of the Institute of Pathology Basel and the Hammersmith Hospital, London, our collection of PTLDs contains 130 cases, one of the worldwide largest such collection.

Title of the project: Evaluation of the efficiency of the isolated lung perfusion with chemotherapy on a murine model of lung metastases from human colorectal cancer.

Place of the training course: Latner Thoracic Surgery Research Laboratories,
Toronto General Hospital,
Toronto, Canada

Summary of the project: The lung is a frequent metastatic site for colorectal cancers. The surgical resection of lung metastases preceded or followed by a systematic chemotherapy allows a curative intent for a minority of patients and around 40 % will develop recurrences linked to the presence of micrometastases. The isolated lung perfusion of chemotherapy temporarily excluded from the systematic circulation, allow delivering doses of chemotherapy to the lung without systematic side effects.
The objective of this work will be to evaluate the efficiency of the perfusion of chemotherapies usually used in human metastatic colorectal cancer on a murin model of lung metastases from human colorectal cancer (athymic nude rat). We will compare the efficiency of isolated lung perfusion of oxaliplatin, 5 Fluoro-uracil, irinotecan, raltitrexed, with the perfusion of gemcitabine and with the intravenous perfusion of targeted therapies.

Title of the project: Correlation between clinico-pathological and molecular analysis in combined hepatocellular-cholangiocarcinoma classical type and «stem cell features» subtypes.

Place of the training course: King's College Hospital, Institute of Liver Studies, London, UK.

Summary of the project: Combined hepatocellular–cholangiocellular carcinomas (cHCC-CC) represent 1% of primary liver cancers and are associated with a poor prognosis. The recent WHO classification for cHCC-CC distinguishes 2 categories of cHCC-CC: cHCC-CC classical type and cHCC-CC with « stem cell features ». The development of cHCC-CC in the context of cirrhosis or non cirrhotic liver and difference in morphology between cHCC-CC classical type and CHCC-CC with "stem cell features" suggest different pathways of carcinogenesis. The aim of this study is to identify genetic mutations in cHCC-CC, using next generation sequencing and to correlate genetic alterations with clinico-pathological data.
This project will provide information regarding the pathogenesis of cHCC-CC classical type and "stem cell features" subtypes and allow potential identification of therapeutical targets.

Title of the project: Deciphering the impact of tumor metabolic microenvironment, on efficacy and side effects of Adoptive Cell Therapy

Place of the training course: Memorial Sloan Kettering Cancer center, Center for cell Engineering. New York City. United state of America

Summary of the project: CD8+ T lymphocytes are critical for protective immunity against intracellular pathogens and tumors. Upon recognition of antigenic peptide-MHC complex, CD8 T cells undergo rapid expansion and differentiate either into highly cytotoxic short live effector cells or memory cells with self-renewal skills. Cell fate decision is strongly influenced by integration of signals delivered through TCR and metabolite sensors. However, in the large majority of patients, this natural defense mechanism is blunted by the immunosuppressive microenvironment. The possibility to engineer autologous T cells easily ex vivo with gene transfer technology allows the development of new immune strategies bypassing the barriers of active immunization to treat cancer patients. Stable expression of Chimeric Antigen receptor (CAR), redirects the specificity of T cells against a selected target and allows the recognition and the eradication of tumor. The most investigated target is the CD19 expressed in B cell lineage. Clinical trials with CAR-CD19 T cells have shown impressive responses in patients with refractory B cell malignancies. Clinical responses were unfortunately associated with a severe cytokine release syndrome due to overwhelming T cell activation. Moreover, in more than 40% of patients, disease relapses within 1 year due to lack of persistence of transferred T cells. Within this project, we propose to define the impact of the tumoral metabolic restrictive environment on CAR- redirected T cell skills.